THE  RELATION  BETWEEN  PHYSICAL  PROPERTIES  AND 
PHYSIOLOGICAL  ACTION  OF  CERTAIN 
LOCAL  ANESTHETICS 


BY 

CHARLES  HEMAN  PEET 
A.  B.  Hope  College,  1914 


THESIS 

Submitted  in  Partial  Fulfillment  of  the  Requirements  for  the 

Degree  of 

MASTER  OF  SCIENCE 

IN  CHEMISTRY 
IN 

THE  GRADUATE  SCHOOL 
OF  THE 

UNIVERSITY  OF  ILLINOIS 


1921 


m\ 


UNIVERSITY  OF  ILLINOIS 


THE  GRADUATE  SCHOOL 

June  4,  i q~)  1 

I HEREBY  RECOMMEND  THAT  THE  THESIS  PREPARED  UNDER  MY 
SUPERVISION  by  Charles  hem  an Peet 

ENTITLED  The  Relation  Eetween  Physical  Properties  and 

__ Physiological  Action  of  Certain  Local  Anesthetic s . 

BE  ACCEPTED  AS  FULFILLING  THIS  PART  OF  THE  REQUIREMENTS  FOR 
THE  DEGREE  OF Ma-ater  -of--- Soi one-e-.-- 


Recommendation  concurred  in* 

Committee 

on 

Final  Examination* 


*Required  for  doctor’s  degree  but  not  for  master’s 

^73  6 37 


' 


\ 


Digitized  by  the  Internet  Archive 
in  2015 


https://archive.org/details/relationbetweenpOOpeet 


CONTENTS 


Page 

I.  INTRODUCTION  1 

II.  HISTORICAL  PART  3 

III.  THEORETICAL  PART  7 

(a)  Theories  Regarding  the  Causation  of  Anesthesia.  7 

(1)  The  Asphyxiation  Theory  7 

(2)  The  Catalase  Theory  7 

(3J  The  Residual  valence  Theory  7 

(4)  The  Overton  Hypothesis  7 

(5)  Lillie’s  Theory  of  Varying  Permeabilities  8 

(b)  Methods  for  the  Preparation  of  Secondary  Amines . 9 

A.  Methods  Applicable  to  Dimethyl  Amine  Only  9 

(1)  Kypohalous  Acid  on  Trimethyl  Amine  9 

(2)  Forma ldehyde-NH^Cl  Condensation  9 

B.  Methods  Which  are  Quite  Generally  Applicable  9 

(1)  Ketone-NK,  Condensation  9 

(2)  Nickel  Reduction  of  Ketoximes  9 

(3)  Alcohol-Ammonia  condensation  9 

(4)  Alcohol-Ammonia  Condensation  9 

(5)  Reduction  of  Nitriles  10 

(6)  Brom-cyanogen  on  Tertiary  Amines  10 

(7)  Dialkyl  Sulfate — Calcium  Cyanamide 

Condensation  10 

(8)  Hydrolysis  of  Sulfonamides  10 

(9)  Alkyl  Halide -Ammonia  condensation  10 

(10)  Hydrolysis  of  Para  nitroso  Amilines  10 

(c)  Methods  for  the  Preparation  of  Amino  Alcohols.  11 

(1)  Chlorhydrin  Condensation  11 

(2)  Ethylene  Oxide  Condensation  11 

(d)  Methods  for  the  preparation  of  Dialkamino  Alkyl  Esters 

of  Para  Amino  Benzoic  Acid.  12 

(1)  Condensation  of  Secondary  Amine  with  Halogen 

Ester  12 

(2)  Condensation  with  Ethyl  Para  Nitro  Benzoate  12 

(3)  Condensation  v/ith  Ethyl  Para  Amino  Benzoate  12 

(4)  Esterification  of  Para  Nitro  Benzoic  Acid  12 

(5)  Esterification  of  para  Amino  Benzoic  Acid  13 

(6)  Reduction  of  para  Azobenzoic  Alkamino  Esters  13 


page 

(7)  Condensation  of  Secondary  Amine  with 

halogen  aster  13 

(8)  Condensation  of  Secondary  Amine  with 

Halogen  Ester  13 

(9)  Esterification  of  Para  Nitro  Benzoyl 

Chloride  13 

(10)  Esterification  of  Para  Nitro  Benzoyl 

Chloride  13 

IY.  EXPERIMENTAL  PART  15 

(a)  preparation  of  Dimethyl  Amino  Ethyl  para  Amino  Benzoate 

Monohydrochloride.  15 

(1)  Preparation  of  Dimethyl  Amine  15 

(2)  Preparation  of  Ethylene  Oxide  16 

(3)  Preparation  of  Dimethyl  Amino  Ethyl  Alcohol  17 

(4)  Preparation  of  Nitro  Benzoyl  chloride  17 

(5)  preparation  of  Dimethyl  Amino  Ethyl  para 

Nitro  Benzoate  Hydrochloride  18 

(6)  Preparation  of  Dimethyl  Amino  Ethyl  para 

Amino  Benzoate  18 

(7)  preparation  of  Dimethyl  Amino  Ethyl  para 

Amino  Benzoate  Monochlorhydrate  19 

(b)  Preparation  of  Dinormal  Amyl  Amino  Ethyl  para  Amino 

Benzoate  Monochlorhydrate  20 

(1)  Preparation  of  Dinormal  Amyl  Amine  20 

(2)  Preparation  of  Dinormal  Amyl  Amino  Ethyl 

Alcohol  21 

( 3 ) Preparation  of  Dinormal  Amyl  Amino  Ethyl 

Para  Nitrobanzoate  Hydrochloride  21 

(4)  Preparation  of  Dinormal  Amyl  Amino  Ethyl 

Para  Amino  Benzoate  - 22 

(5)  Preparation  of  Dinormal  Amyl  Amino  Ethyl 

Para  Amino  Benzoate  Monochlorhydrate  23 

(c)  preparation  of  Diiso  Amyl  Amine.  23 

Y.  SUMMARY  25 

VI.  BIBLIOGRAPHY  26 


THE  RELATION  BETWEEN  PHYSICAL  PROPERTIES 


AND 

PHYSIOLOGICAL  ACTION  OF  CERTAIN  LOCAL  ANESTHETICS 
I.  INTRODUCTION. 

Tho  the  synthesis  of  many  local  anesthetics  has  been  achieved  and  many 
theories  have  been  advanced  to  explain  their  activity,  few  attempts  at  serial 
studies  of  anesthetic  compounds  and  the  relation  between  their  chemical  consti- 
tutions, physical  properties  and  physiological  activities  are  recorded.  These  re- 
searches have  been  instituted  with  a view  to  producing  an  extensive  anesthetic 
series  and  obtaining  such  relationships  in  the  hope  that  the  results  would  yield 
some  confirmation  of  one  or  another  of  the  theories  as  well  as  afford  some  logical 
basis  upon  which  to  predict  the  probable  anestheticity  of  similar  compounds. 

The  particular  series  upon  which  these  researches  have  been  undertaken  is 
composed  of  the  di-alkyl  amino  esters  of  para  amino  benzoic  acid.  It  is  planned 
to  synthesize  the  di-alkyl  amino  ethyl,  di-alkyl  amino  propyl,  di-alkyl  amino 
butyl,  and  di-alkyl  amino  amyl  esters  in  which  the  di-alkyl  groups  shall  be  methyl, 
ethyl,  propyl,  iso-propyl,  butyl,  iso-butyl,  amyl,  iso-amyl,  allyl,  heptyl  and 
lauryl.  The  present  paper  will  deal  only  with  the  methyl,  amyl  and  iso-amyl  com- 
pounds. Certain  other  members  of  the  projected  series  will  be  reported  by  Burnett 
and  Jenkins  and  further  studies  will  be  made  and  reported  later. 

The  usual  physical  constants  of  these  compounds  — melting  points,  speci- 
fic gravities  and  refractive  indices  — will  be  determined  and  in  addition  it  is 
desired  to  determine  their  lipoid-water  partition  coefficients,  the  conductivity 


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of  their  solutions,  their  effect  on  the  permeability  of  cell  membranes,  the  sur- 
face tensions  of  their  solutions  and  their  effects  on  colloids. 

The  pharmacodynamic  properties  of  the  members  of  the  series  — principal- 
ly their  specific  ana sthetici ties  and  their  toxicities  — will  be  determined  else- 
where and  reported  later. 


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3 


II.  HISTORICAL  PART. 

The  most  generally  used  local  anesthetic  was,  for  many  years,  cocain. 

This  was  isolated  from  cocoa  leaves  by  Niemann1  in  I860,  in  the  years  just  prior 
2 

to  1900  Einhorn  proved  it  to  be  H 


which  might  also  be  written 


3 4 

Merck’s  earlier  works,  1885,  and  Willstaetter ’s  synthesis  of  cocain,  1903,  gave 

complete  confirmation  to  this  structure. 

As  the  second  manner  of  writing  the  formula  very  clearly  indicates,  cocain 
is  an  alkamino  ester  of  benzoic  acid.  This  suggested  to  Einhorn  * that  the  ester 
grouping  might  be  responsible  for  the  production  of  anesthetic  properties.  He  was 
able  to  verify  this  hypothesis  but  found  that  the  degree  of  anestheticity  was  ex- 
tremely variable.  It  appeared,  then,  that  there  must  be  some  relation  between  an- 
esthetic strength  and  the  structure  of  the  side-chain. 


. 


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• •: 


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'x  'k  • fL  . i.  c 


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• ‘ • - r ‘ ‘ ' ' * ..  . '■  :v  • i 'J  • : . . .v  . 

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J ’ 1 . J ; t J . j ■ . 

. :i  ft-  L . i.  : • . ’ it 


4 


# 

Highly  anesthetic  effects  were  produced  by  Eucain  a 


5,6 


and  its  free  base: 


which  was  synthesized  by  Vinci.  But  this  has  a cyclic  side  chain  which  is  of  much 

the  same  order  of  complexity  as  that  of  cocain. 

In  an  attempt  to  simplify  the  side  chain  to  determine  the  effect  of  such 

8 

simplification  upon  anestheticity,  Einhorn  and  Pyle  synthesized  Orthoform 


and  Orthoform  (new) 

/ 

— c - och3 

These  proved  very  satisfactory  anesthetics  when  applied  to  open  wounds 
and  they  were  very  soon  widely  used  as  dusting  powders  but  their  insolubility  lim- 
ited their  applicability. 

5 

To  remedy  this  defect,  Einhorn  and  his  associates  turned  their  attention 
to  the  alkamino  esters  of  benzoic  acid.  These  were,  as  the  free  esters,  quite  as 
insoluble  as  esters  of  the  type  just  mentioned  but  their  acid  salts  were  very  sa- 
tisfactorily soluble.  Phaimacological  tests  showed  that  the  physiological  effects 
of  these  salts  were  undesirable , however,  because  of  their  acidity.  This  was 
counteracted  by  the  introduction  of  an  amino  group  into  the  ring. 

Because  the  position  of  the  nitrogen  on  the  ring  appeared  to  be  of  no 


consequence  and  because  the  para-amino  compound  was  most  easily  obtained,  it  was 


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5 


para  amino  benzoic  esters  upon  which  Einhom  and  his  associates  worked,  in  this 
series,  the  dimethyl  amino  ethyl  diethyl  amino  ethylrdiiso  propyl  amino  ethyl 
diiso  butyl  amino  ethyl  - and  diiso  amyl  amino  ethyl  para  amino  benzoates  v/ere  syn- 
thesized. 

The  melting  points,  specific  gravities  and  refractive  indices  of  these 
compounds  were  determined  and  certain  physiological  tests  were  applied.  Not  enough 
work  was  done,  however,  to  demonstrate  any  relations  between  the  three  phases  of 
the  question  which  it  is  the  intent  of  these  papers  to  study. 

Of  the  series  thus  synthesized,  the  monochlorhydrate  of  the  diethyl  aster 
showed  the  widest  applicability  on  account  of  the  low  ratio  between  its  toxicity 
and  anesthet icity  as  well  as  because  of  its  comparative  ease  and  cheapness  of  pre- 
paration. it  is  known  variously  to  physicians  and  chemists  as  "procaine"  or«novo- 
caine". 

These  compounds  differ  from  cocaine  not  only  in  the  lesser  complexity  of 

the  groupings  about  the  tertiary  N but  also  in  the  distance  of  this  N from  the 
9 

ring.  Kamra  conceived  the  idea  that  the  three  - carbon  linkage  might  be  signifi- 
cant. To  determine  the  truth  of  this  assumption,  they  synthesized  di  ethyl  amino 
propyl  para  amino  benzoate  and  found  that  its  increased  anestheticity  over  pro- 
caine substantiated  their  theory. 

Now  the  diethyl  esters  had  given  high  anestheticity  and  low  toxicity  but 
increasing  the  weight  of  the  side  chain  by  the  introduction  of  forked  (iso)  chains 
seemed  not  to  accent  anesthetic  power  and  did  seem  to  increase  toxicity.  To  de- 
termine whether  this  relationship  were  due  to  the  presence  of  the  forked  chain, 
Kamm,  Adams  and  Volwiler10,  synthesized  di  normal  butyl  amino  propyl  p-amino  ben- 
zoate. Pharmacological  tests  showed  its  monochlorhydrate  to  have  about  the  same 
toxicity  as  that  of  cocaine  but  an  anestheticity  from  two  and  a half  to  three 


6 


times  as  great.  Hence  it  offers  very  desirable  qualities  as  a substitute  for 
cocaine.  It  is  already  finding  rather  wide  application  among  physicians  and  sur- 
geons under  the  name  of  "butyn”. 

But  with  these,  as  with  the  series  synthesized  by  Einhorn,  investigation 
of  the  physical  properties  has  been  deferred. 


7 


III.  THEORETICAL  PART. 

(a)  Theories  regarding  the  causation  of  anesthesia. 

(1)  Verworn^  believes  that  anesthesia  is  produced  thru  the  inability 
of  the  cell  to  carry  on  its  normal  oxidation  processes,  so  long  as  these  are  in- 
hibited, the  cell  lies  dormant  or  is  in  a state  of  anesthesia  but  with  the  return 

I 

of  its  ability  to  exhibit  oxidation  processes,  i.e.,  w ith  the  passing  of  the  ef- 
fects of  the  anesthetic,  feeling  returns.  He  does  not  appear  to  ascribe  this  re- 
duction in  oxidation  rate  to  any  definite  source. 

12 

(2)  Burge  has  advanced  a theory  very  similar  to  that  held  by  Verwom 
but  ascribing  the  decrease  in  oxidation  rate  to  a specific  action  upon  a specific 
agent  — catalase.  He  maintains  that  this  enzyme  is  either  destroyed  or  its  action 

is  strongly  inhibited  by  anesthetics. 

13 

(3)  Mathews  has  suggested  the  possibility  of  a molecular  union  between 
anesthetic  and  protoplasm  due  to  the  residual  valencies  of  both.  He  believes  mole- 
cular oxygen-protoplasm  compounds  or  perhaps  a peroxide  protox>lasm  similar  to  oxy- 
haemoglobin  to  be  the  irritable  substance  of  protoplasm.  Normally,  stimulation 
produces  oxidation  and  a rearrangement  of  the  unstable  molecular  union  to  a more 
stable  form  with  the  liberation  of  C09  but  anesthetics  occupy  the  oxygen  receptors 
of  the  cell  forming  a non- irritable , dissociable,  protoplasmic  compound.  This  con- 
dition  is  anesthesia. 

Mathews  claims  to  have  traced  a general  parallelism  between  anesthetic 
strength  and  residual  valency  but  too  little  research  has  been  carried  on  in  this 
direction  to  bring  the  theory  general  credence. 

(4)  It  had  been  proven  that  the  nerve  cells,  which  are  the  specific  parts 
of  the  organism  affected  by  the  type  of  drug  under  consideration,  contained  cer- 


8 


tain  fats,  lecithin  and  cholesterol,  in  considerable  amounts  in  rather  marked  con- 
tradistinction to  blood,  lymph  and  muscle  fibre.  Prom  this  fact  Overton^  and 
15 

Meyer  elaborated  the  theory  that  anesthetics  must  be  fat  soluble  and  that  their 
anestheticity  is  a function  of  their  distribution  ratios  between  oil  and  water  — 
water  being  comparable  to  blood. 

This  begs  the  question  as  to  how  anesthesia  is  produced  but,  if  true, 

provides  a criterion  by  which  the  strength  of  an  anesthetic  may  be  predicted. 

16 

(5)  Lillie  holds  that  the  effect  of  the  anesthetic  is  essentially 

17 

physical,  affecting  intersurface  activities  especially.  As  Winterstein  summar- 
izes the  theory,  "The  adsorption  of  the  narcotic  by  the  cell  colloids  causes  a re- 
versible decrease  in  the  permeability  of  the  cell  surface  for  water  and  soluble 
constituents,  and  thereby  determines  a diminution  or  abolition  of  the  excitability 
associated  with  normal  permeability  conditions,  in  higher  concentrations  an  ir- 
reversible increase  of  permeability  occurs,  which  is  probably  dependent  on  a dim- 
inution in  the  degree  of  dispersion  of  the  cell  colloids.  There  is  no  occasion  to 

assign  a decisive  role  to  the  lipoids  in  this  mechanism." 

18 

Clowes  extends  this  theory  to  the  point  which  it  is  planned  to  in- 
vestigate in  these  papers  when  he  says  that,  if  sound,  it  should  be  perfectly  ap- 
plicable to  purely  physical  systems.  As  the  result  of  his  studies  of  such  systems 
he  says,  "It  appears  possible  that  protoplasm  is  an  aqueous  fatty  system  and  that 
anesthetics  function  by  promoting'  the  continuity  of  an  external  fatty  or  lipoid 
phase.  The  solubility  of  this  lipoid  film  in  adjacent  aqueous  phases  being  lower- 
ed, its  permeability  to  v/ater  soluble  substances  would  be  diminished.  Since  cer- 
tain vital  processes  presumably  depend,  upon  intermittent  intercommunication  betweer 
adjacent  aqueous  phases,  it  may  well  be  imagined  that  a temporary  interruption  in 


9 


this  communication  would  result  in  anesthesia." 

(b)  Methods  for  the  preparation  of  secondary  amines. 

A.  Methods  applicable  to  dimethyl  amine  only. 

(1)  The  action  of  a hypohalous  acid  on  tertiary  methyl  amine  yields  a 
halogen  substituted  amine, 

CHr, 


:N  - Cl, 


CH, 


which  can  be  reduced  to  the  secondary  methyl  amine  by  sodium  bisulfite. 


19 


(2)  The  condensation  of  three  parts  of  formaldehyde  (paraformaldehyde) 

20 

with  one  part  of  UH^Cl  gives  very  satisfactory  yields  of  dimethyl  amine  according 
to  T7emer. 

B.  Methods  which  are  quite  generally  applicable. 

21 

(1)  Loeffler  reports  the  synthesis  of  secondary  amines  by  the  action 
of  on  symmetric  ketones  and  the  reduction  of  the  resulting  ketoxime  by  sodium 


and  alcohol. 


22 


(2)  Mailhe  has  employed  the  catalytic  method  of  reducing  ketoxime s 

with  hydrogen  over  nickel  quite  successfully. 

23 

(3)  Merz  and  Gasiorowski  succeeded  in  obtaining  secondary  amines  by 

heating  the  alcohol  and  ammonia  with  zinc  chloride  in  an  autoclave  to  rather  high 

temperatures,  it  is  probable  that  the  yield  of  secondary  amine  would  be  increased 

if  primary  amine  were  employed  instead  of  ammonia. 

24 

(4)  Sabatier  and  Mailhe  by  a method  somewhat  similar  to  that  of  Merz 
and  Gasiorowski  obtained  secondary  amines  from  alcohol  and  ammonia  but  they  used 
thorium  or  tungsten  dioxides  instead  of  ZnCl9. 


l 


. .A 


. i 


• * * 


10 


25 

(5)  Sabatier  and  Sanderens  were  able  to  reduce  aliphatic  nitriles  to 
secondary  amines  by  H over  nickel  at  temperatures  from  250°  to  300°. 

(6)  By  the  reaction  between  tertiary  amines  and  brom-cyanogen  to  form 

the  addition  product,  B^N-BrCN , the  splitting  out  of  KBr  and  the  reduction  of  the 

26 

nitrile  thus  formed,  von  Braun  obtained  secondary  amines. 

27,28 

(7)  Traube  and  Englehardt  found  that  if  dialkyl  sulfate  was  re- 

fluxed with  calcium  cyanamide  a 70  - 80%  yield  of  H^NCN  resulted.  From  this  nitrile 
the  amine  could  be  obtained  by  methods  previously  described. 

(8)  Hydrolysis  of  substituted  sulfonamides  by  SO^OHCl  gives  secondary 
29 

amines. 

30 

(9)  Hofmann  in  1849  reported  the  synthesis  of  primary,  secondary  and 

tertiary  amines  by  the  condensation  of  alkyl  halide  with  NHg.  This  is  an  autoclave 

reaction  and  it  is  difficult  to  control  the  conditions  so  as  to  yield  the  specific 

31 

amines  desired.  Vander  zande  modified  this  method,  by  the  use  of  a primary  amine 
instead  of  ammonia.  He  was  thus  able  to  increase  the  yields  of  secondary  amines. 

(10)  The  hydrolysis  of  p-nitroso  anilines  by  dilute  alkalies  splits  off 
the  secondary  amine  very  readily  where  nitrosation  is  possible. 

Of  these  methods,  that  of  hydrolysis  of  p-nitroso  dimethyl  aniline  ap- 
peared most  desirable  for  the  preparation  of  dimethyl  amine  because  of  the  cheap- 
ness of  dimethyl  aniline,  the  ease  with  which  it  can  be  nitrosated  and  the  ease 
with  which  it  can  be  split.  The  method  should  be  quite  applicable  to  the  more  com- 
plex amines  as  well  but  considerable  study  of  the  conditions  of  the  reaction  is 
necessary  to  insure  its  success.  For  this  reason,  Vander  zande’ s modification  of 
the  Hofmann  condensation  was  adopted  for  the  preparation  of  the  di-iso  amyl  and 
di-normal  amyl  amines. 


11 


(c)  Methods  for  the  preparation  of  amino  alcohols. 


Amino  alcohols  may  be  considered  as  primary  or  secondary  amines  in  which 
one  H has  been  replaced  by  ROH.  The  simplest  are  the  amino  alcohols  themselves  of 
which  amino  ethyl  alcohol,  NH^-CH^-CH^OH , is  typical. 

(1)  This  may  be  made  by  condensing  ethylene  chlorhydrin  with  ammonia,^ 


ch2ci-ch2oh  +■  nh3 


CHo-NHp-HCl 

I 2 

CH20H 


and  freeing  the  base  with  NaOH.  Exactly  similar  reactions  occur  for  primary  and 
secondary  amines 


CH9C1 

CHr,-HHR--ECl 

1 " 

+ 

RNHp  

I 2 

CH20H 

CH  OH 

CHqC1 

1 & 

+ 

CH  -H^-HC1 

1 

bjsh  

CH20H 

£ 

CH2GH 

hence  the  method  was  used  by  Eihhom  in  the  synthesis  of  his  amino  alcohols  of 

4 

secondary  amines.  He  obtained  good  results  but  by  the  methods  used  in  this  labor- 
atory no  satisfactory  yields  were  obtained  in  the  case  of  the  condensation  with  di- 
methyl amine  so  the  method  was  temporarily  abandoned.  It  seems  probable,  however, 
that  at  higher  temperatures  and  under  pressure  in  an  autoclave  better  yields  may 
be  obtained. 

ag 

(£)  Wurtz  found  that  the  condensation  of  ammonia  with  ethylene  oxide 

proceeded  very  smoothly  and  with  few  complications.  The  reaction: 

CHP  CHkNHo 

I ~^0  + HaNH  | * * 

CHa  CH^OH 

in  presence  of  excess  (CH2)20,  complex  condensations  of  the  types 
H2N-CH2-CH2-0-CH2-CH2-0CH2-CH20H,  etc. 

♦ 


f V 


' ■ 

- 


' 

. ' . ~ l h 


i 


I l> 


1 ' 


• ! ■ 


. 


I* 


• r r 


I 


'! 


n 


. i 

' ■ - ’ • < 


' ( 


♦ 


12 


are  possible.  Exactly  similar  reactions  and  results  are  obtained  with  amines  but 
with  practically  theoretical  amounts  of  amine  and  ethylene  oxide,  an  excellent  pro- 
duct  is  obtained  in  good  yields. 

An  objection  to  this  method  lies  in  the  low  boiling-point  of  the  (CH9)90 
and  the  consequent  necessity  for  sealing  the  capsule  of  oxide  in  a pressure  tube 
for  the  reaction.  It  appears,  too,  that  the  reaction  between  perfectly  dry  amine 
and  oxide  is  very  slow  and  requires  a rather  high  temperature.  The  presence  of 
even  small  amounts  of  water,  however,  seems  to  catalyze  the  reaction  and  less  time 
at  lower  temperatures  is  sufficient  to  bring  the  reaction  to  practical  completion. 

It  also  appears  that  the  condensation  of  the  higher  amines  proceeds 
more  smoothly  than  that  of  the  lower. 

(d)  Methods  for  the  preparation  of  di-alkamino 
alkyl  esters  of  para  amino  benzoic  acid. 

(1)  The  secondary  amine  can  be  condensed  with  a halogen  ester  formed 
by  the  reaction  between  sodium  para  nitro  benzoate  and  an  ethylene  halide  . The 
nitro  ester  thus  obtained  yields  the  desired  amino  ester  upon  reduction. 

(2)  Methyl  para  nitro  benzoate  can  be  condensed  with  the  proper  di- 

37 

alkamino  alcohol,  ethyl  alcohol  splitting  out  , and  the  resulting  nitro  ester  can 
be  reduced  as  above. 

(3)  Methyl  para  amino  benzoate  can  be  condensed  with  a dialkamino  alco- 

38 

hoi  in  the  same  manner  as  the  p-nitro  benzoic  ester  . 

(4)  Para  nitro  benzoic  acid  can  be  esterified  with  amino  ethyl  alcohol. 
The  amino  hydrogens  can  then  be  substituted  by  alkyl  groups  by  means  of  a modifi- 
cation of  the  Hofmann  reaction.  This  nitro  ester  yields  the  amino  ester  on  reduc- 


39 

tion  . 


•» 


, 


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. 'I  . ! . , ' . ! 


' 


■ ' 

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I < ’ 

. ? 


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i 


13 


(5)  In  similar  manner  to  the  esterification  of  para  nitro  benzoic  acid 

40 

with  amino  ethyl  alcohol,  p-amino  benzoic  acid  may  be  esterified  and  converted 

31 

into  the  dialkamino  ester  by  Vander  zande ' s method. 

41 

(6)  in  the  laboratories  of  the  Hoechster  Farbwerke  it  was  found  that 
the  alkamino  ester  of  p-azobenzoic  acid  which  had  been  formed  by  the  esterifica- 
tion of  the  azobenzoic  acid  or  the  condensation  of  the  p-azobenzoyl  chloride  with 
dialkamino  alcohol  could  be  reduced  to  yield  two  molecules  of  dialkamino  p-amino 
benzoate . 


+■  4 H 


(7)  Para  nitro  benzoic  acid  can  be  esterified  with  ethylene  chlorhydrin 

4£ 

to  give  a halogen  ester  which  can  be  condensed  with  a secondary  amine  as  herein- 
before described.  The  amino  ester  is  obtained  upon  reduction. 

(8)  In  manner  very  similar  to  that  described  in  (7)  para  amino  benzoic 
acid  can  be  esterified  with  ethylene  chlorhydrin  and  then  condensed  with  the  sec- 
ondary amine43. 

(9)  Para  nitro  benzoyl  chloride  can  be  esterified  with  ethylene  chloro- 
hydrin44  and  the  required  amino  groups  can  then  be  introduced  as  described  in  (7). 

(10)  The  para  nitro  benzoyl  chloride  can  be  condensed  at  once  with  the 

45 

dialkamino  alcohol  and  the  resulting  nitro  ester  can  be  reduced  to  give  the  de- 
sired amino  ester. 

Tho  all  of  these  methods  are  described  in  the  literature,  few  of  them 
are  of  direct  practical  importance.  The  condensation  of  a secondary  amine  with 


14 


halogen  ester  Is  quite  practicable  but  has  not  been  employed  in  the  syntheses  de- 
scribed in  this  paper  because  of  the  still  greater  ease  with  which  the  acid  chlor- 
ides can  be  esterified.  The  sensitivity  of  the  amino  group  makes  the  use  of  the 
nitro  compound  and  its  subsequent  reduction  preferable.  The  principal  objection 
to  be  urged  against  this  latter  method  is  the  danger  of  hydrolyzing  the  nitro 
ester  and  so  reducing  the  yield  but  with  care  this  can  be  kept  at  a minimum. 

Practically  any  reducing  agent  should  serve  but  tin  and  hydrochloric 
acid  or  zinc  and  HGl  have  been  most  commonly  reported  in  the  literature.  They 
yield  a very  nice  product  but  it  is  not  always  easy  to  separate  this  product, 
iron,  tho  the  product  is  less  desirable  than  that  from  tin  or  zinc  reductions,  is 
not  only  much  cheaper  but  is  more  readily  extracted  so  it  was  decided  to  attempt 
to  employ  it  as  a reducing  agent. 


• x V*  t 


...  - < . *. 

' • ‘ 

' 

i i . 

t 

, 

r - 

. ■ f • : 


15 


IV.  EXPERnaSNTAL  PAST. 

(a)  preparation  of  di-methyl  amino  ethyl 
para  amino  benzoate  monohydrochloride. 

(1)  Preparation  of  dime  thy lamine . 

The  method  employed  in  this  synthesis  was  the  nitrosation  of  dimethyl 
aniline  and  the  hydrolysis  of  the  resulting  nitroso  compound. 

The  nitrosation  was  performed  by  adding  72  g.  of  commercial  NaNO  in 

2 

saturated  solution  to  a mixture  of  120  g.  of  dimethyl  aniline,  270  c.c.  cone.  HCl 
and  600  c.c.  HO.  The  aniline  hydrochloride  was  cooled  to  about  0°  C.  before  the 
NaHOr,  was  added.  This  addition  was  carried  on  very  slowly  by  means  of  an  automa- 
tic dropping  funnel  and  the  reaction  mixture  was  kept  thoroly  agitatad  by  a mech- 
anical stirrer.  Care  was  taken  to  keep  the  temperature  below  5°  C.,  higher  temp- 
eratures having  been  proven  to  decrease  the  yields.  The  p-nitroso  dimethyl  anilin 
nydrochlor ide  crystallized  out  in  orange-red  to  green  crystals. 

No  attempt  was  made  to  isolate  this  product  or  to  determine  its  per- 
centage yield  but  the  flask  was  immediately  connected  to  a long  reflux  condenser. 
Thru  this  condenser  1600  c.c.  of  10$  NaOK  were  introduced  and  the  reflux  was  con- 
nected with  a spiral  ice  condenser.  There  was  no  evidence  of  formation  of  di- 
methyl amine  until  the  boiling  point  of  the  reaction  mixture  was  reached.  As  soon 
as  the  amine  began  to  come  over,  however,  its  distillation  was  very  rapid  and  in 
about  an  hour  the  reaction  was  complete. 

120  g.  of  dimethyl  aniline  yielded  15.75  g.  (35$)  and  20.6  g.  (45$) 
of  dimethyl  amine.  The  difficulties  attendant  upon  collecting  the  amine  which 
boils  at  7°  — 7.5°  0.  probably  account  for  some  part  of  the  failure  to  reach  more 


16 


nearly  theoretical  yields.  It  also  seems  probable  that  some  of  the  amine  remained 
dissolved  in  the  rather  large  amount  of  solution  employed. 

The  amine  thus  obtained  was  usually  somewhat  colored.  Run  thru  a dry- 
ing train  (soda  lime),  however,  it  could  be  collected  as  a clear,  colorless  liquid 
of  extremely  penetrating  ammoniacal  odor. 

(2)  Preparation  of  ethylene  oxide. 

NaOH  splits  out  HCl  very  easily  from  ethylene  chlorhydrin  to  form  the 
cyclic  ether 


It  would  appear  immaterial  whether  the  alkali  be  added  to  the  chlorhydrin  or  the 
reverse  but  considerably  better  yields  were  obtained  by  the  latter  procedure. 

100  c.c.  of  GHgCl-CHgOH  were  put  in  a flask  which  was  connected  with 
a spiral  ice  condenser.  Saturated  NaOH  solution  was  added  rather  slowly  by  an 
automatic  dropping  funnel  and  a little  heat  was  applied  to  start  the  reaction.  A 
vigorous  evolution  of  ethylene  oxide  soon  began  and  NaOH  was  added  continuously 
until  this  reaction  ceased. 

The  (CHgJ^O  was  caught  in  ice-jacketed  tubes  which  were  sealed  off  be- 
fore removal  from  the  ice.  in  this  way  36.15  g.  of  ethylene  oxide  (b.p.  12.5° } 
or  53.4$  theoretical  was  obtained. 

By  reversing  the  process  and  adding  CHgCl-CH^OH  to  saturated  NaOH  and 
heating  gently,  22  g.  of  chlorhydrin  gave  8 g.  or  66$  theoretical  of  the  oxide. 
Besides  giving  better  yields,  this  method  is  more  desirable  because  it  does  not 


17 


expose  the  stop-cocks  of  the  dropping  funnels  to  the  action  of  strong  alkali. 

(3)  preparation  of  dimethyl  amino  ethyl  alcohol. 

26.25  g.  of  dimethyl  amine  were  sealed  with  a slight  excess  (26.8  g.  ) 
of  ethylene  oxide  in  a Carius  tube.  The  capsules  of  (CH3)2NH  and  (CH^J^O  were 
broken  and  the  bomb  was  kept  at  100°  in  a water  bath  for  several  hours.  Distilla- 
tion of  the  condensation  product  gave  5.1  g.  (20%)  of  dimethyl  amino  ethyl  alcohol 
boiling  at  133  - 136°.  (It  should  be  remarked  that  neither  of  the  reactions  in 
this  case  was  anhydrous. ) 

A similar  condensation  was  run  in  the  presence  of  2 c.c.  of  water,  in 
this  tube  it  was  observed  that  considerable  heat  was  evolved  as  soon  as  the  inner 
capsules  were  broken.  The  tube  was  then  immersed  in  a water  bath  as  before  but 
only  for  a few  hours  and  from  30.2  g.  of  (CH3)2KH  11.1  g.  of  (CH3 J^N-CEg-CH^OH 
boiling  very  sharply  at  135°  were  obtained. 

Tho  this  was  a yield  of  only  18.6%,  the  heat  generated  when  the  cap- 
sules were  broken  and  the  comparatively  short  time  allowed  the  reaction  indicates 
the  catalytic  action  of  water  in  this  reaction.  Other  ethylene  oxide  condensa- 
tions indicate  that  much  better  yields  would  have  resulted  had  higher  temperatures 
been  employed. 

(4)  Preparation  of  para  nitro  benzoyl  chloride. 

100  g.  of  p-nitro  benzoic  were  intimately  mixed  with  125  g.  of  PCI5 
and  heated  on  a water  bath.  As  soon  as  the  reaction  had  ceased,  the  mixture  of 
p-nitro  benzoyl  chloride  and  P0Cl3  was  distilled  under  diminished  pressure  from 
an  oil  bath  (Burnett  and  Jenkins  had  found  difficulties  in  distilling  over  a free 
flame.)  The  POCI3  came  over  first  and  when  the  p-nitro  benzoyl  chloride  began  to 
distil  the  receiver  was  changed.  From  this  distillation  77  g.  (70%)  of  the  acid 


18 


chloride  was  obtained. 


(5)  Preparation  of  dimethyl  amino  ethyl  para 
nitro  benzoate  hydrochloride . 

25.2  g.  of  p-nitro  benzoyl  chloride  were  dissolved  in  dry  benzene  and 
12.1  g.  of  (GH„  )JJ-CH„-CEo0H  were  stirred  into  the  solution.  From  this  mixture 
crystals  began  immediately  to  separate  and  in  a very  short  time  the  whole  was  a 
semi-solid  paste.  Some  heat  was  evolved  during  the  reaction. 

The  excess  benzene  was  filtered  off  and  the  ester  hydrochloride  was 
dried.  The  yield  was  38  g.  or  100$. 

A portion  of  this  salt  was  treated  with  NaOH  and  the  free  ester  was 
purified  by  re crystallization  from  ether.  A finely  crystalline  product  melting 
at  57.5°  was  obtained.  F inhorn* reports  it  as  melting  at  58°  - 59°. 


(6)  preparation  of  dimethyl  amino  ethyl 


para  amino  benzoate 

p 

7.9  g.  of  dry  P-NO2-G5H4-C  - O-CEg-GHg-N^  -HCl  were  made  into  a 


,xGH3 


‘CHc 


paste  with  water  and  about  30  g.  of  powdered  iron  were  added.  The  mixture  was 
thoroly  mixed  and  in  a short  time  it  began  to  become  warm. 

Previous  reductions  had  shown  a marked  decrease  in  the  percentage 
yield  of  the  reduction  product  when  heating  to  much  above  50°  occurred  during 
the  reduction.  Accordingly  the  mixture  was  cooled  by  the  addition  of  a small 
amount  of  ice  and  then  stirred  again  until  the  reaction  had  begun  to  generate 
too  much  heat  when  it  was  again  cooled. 

After  it  appeared  that  the  reduction  had  proceeded  to  completion,  a 
considerable  excess  of  iron  was  added  to  the  mixture  and  it  was  allowed  to 


19 


stand  for  a couple  hours.  A saturated  solution  of  tartaric  acid  was  then  added 
to  acid  reaction  and  the  iron  was  filtered  out.  The  amino  ester  was  carried 
thru  in  the  aqueous  filtrate  as  a soluble  tartrate. 

It  seemed  quite  feasible  to  extract  the  free  ester  directly  from  the 
reduction  mixture  after  rendering  it  alkaline  but  a series  of  attempts  at  such 
extractions  gave  yields  ranging  from  30.3$  to  51.1$  so  it  was  decided  to  follow 
the  tartrate  extraction  method.  It  is  very  probable  that  direct  and  complete 
extraction  would  be  possible  if  the  ether  could  be  more  intimately  mixed  with 
the  iron  reduction  mixture  but  under  the  conditions  obtaining  during  these  ex- 
periments, the  success  of  that  method  seamed  to  be  too  questionable  to  be  fol- 
lowed further. 

Both  the  tartrate  solution  and  the  iron  residues  were  made  alkaline 

with  10$  NaOE,  the  temperature  being  kept  below  40°  - 50°,  and  the  free  ester 

was  extracted  with  ether  giving  a yield  of  4.96  g.  (70.8$).  Upon  recrystalliza- 

o o 

tion  from  ether  it  gave  fine,  white  crystals  melting  at  119.5  to  120  . Ein- 
horn^  reports  the  melting  of  this  ester  as  121°. 

(7)  preparation  of  dimethyl  amino  ethyl  para 
amino  benzoate  monochlorhydrate . 

The  free  ester  was  dissolved  in  ethyl  alcohol  and  titrated  with  alco- 
holic HCl  until  it  was  neutral  to  litmus.  The  resulting  monochlorhydrate  crys- 
tallized with  some  difficulty  on  account  of  the  water  present  and  the  very  con- 
siderable solubility  of  the  salt  in  water.  To  obviate  this  difficulty,  when  the 
ester  had  dried  it  was  recrystallized  from  absolute  alcohol.  It  was  not  found 
necessary  to  salt  out  with  ethyl  acetate  as  suggested  by  Eihhorn^. 


The  ester  resulting  from  recrystallization  could  be  obtained  in 


— 20 

small  amounts  as  very  white,  fine  crystals  but  most  of  the  product  even  after  re- 
peated recrystallizations  had  a decidedly  yellowish  hue.  Its  melting  point  was 
185°  (Einhom^,  185°  - 186°).  On  the  tongue  it  was  somewhat  bitter,  but  there 
was  no  marked  anestheticity  such  as  that  exhibited  by  procaine. 

(b)  Preparation  of  di-normal  amyl  amino  ethyl 
para  amino  benzoate  monochlorhydrate . 

(1)  preparation  of  di-normal  amyl  amine. 

Yander  zande’s  modification  of  the  Hofmann  condensation  was  employed. 
50  g.  of  n-amyl  alcohol  were  refluxed  for  two  and  one-half  hours  with  HBr  con- 
taining some  H^SO^.  This  HBr  was  made  by  passing  SO^  thru  80  g.  of  Br  according 
to  the  method  of  Kamm  and  Marvel^.  After  refluxing,  60  g.  (71%)  of  normal  amyl 
bromide  boiling  between  126°  - 130°  was  obtained. 

The  60  g.  of  CHg-CH^-CHg-C^-CH^Br  thus  prepared  was  mixed  with  the 
theoretical  amount,  34.5  g. , of  the  primary  normal  amyl  amine.  The  flask  was 
stoppered  and  shaken  but  no  heat  was  applied.  In  a short  time  a violent  reaction 
occurred  blowing  the  stopper  and  much  of  the  amyl  amino  halide  formed  in  the  re- 
action out  of  the  flask. 

As  much  of  this  as  possible  was  recovered,  neutralized  with  NaOH , 
separated  and  distilled.  This  distillation  yielded  34.8  g.  of  product  boiling 
over  a considerable  range,  155°  - 185°,  but  too  high  to  be  primary  and  too  low 
to  be  tertiary  amine.  The  yield  of  high  boiling  amine  was  62.7%. 

Because  of  the  very  considerable  difficulty  involved  in  separating 
amines  by  fractionation,  it  was  decided  to  use  this  product  for  condensation 
with  ethylene  oxide  to  form  the  amino  alcohol.  The  tertiary  amine  would  not 


21 

react  and  the  boiling  point  precluded  the  possibility  of  more  than  traces  of  the 
primary  amine . 

47 

Primary  amylamine , b.p.,  103° 

Secondary  amylamine,  b.p.,  186°  - 190° 

Tertiary  amylamine,  b.p.,  238° 

(2)  Preparation  of  di-normal 
amyl  amino  ethyl  alcohol. 

34.8  g.  of  the  high  boiling  n-amyl  amine  was  sealed  with  10.05  g.  of 
(CHP)r>0  and  4 c.c.  of  water  in  a Carius  tube  and  kept  at  100°  in  a water  bath 
for  two  days.  The  contents  did  not  appear  viscous  enough  to  be  the  alcohol  de- 
sired so  the  bomb  was  put  in  an  electric  oven  and  kept  at  about  130°  for  ten 
hours.  It  was  then  opened  and  its  contents  distilled.  No  record  of  this  com- 
pound appears  in  the  literature  but  26.7  g.  of  distillate  boiling  at  from  254° 

to  258°  was  collected.  Since  the  boiling  point  of  di-iso  amyl  amino  ethanol  is 
o 35 

247  - 248°  , it  appeared  probable  that  this  was  the  product  desired. 

A d etermination  of  its  constants  will  be  made  and  reported  later  but 
for  the  present  paper  it  was  most  desired  to  prepare  its  amino  ester  so  those 'de- 
terminations were  deferred.  However,  its  specific  gravity  is  less  than  1 and  it 
appears  that  its  boiling  point  will  be  about  255°  - 258°.  It  is  colorless  and 
has  a faintly  aromatic  odor. 

(3)  Preparation  of  di-normal  amyl  amino  ethyl 
para  nitro  benzoate  hydrochloride. 

26.7  g.  of  the  di-normal  amyl  amino  ethyl  alcohol  made  as  described 
above  v/as  condensed  with  24.64  g.  of  p-nitrobenzoyl  chloride  in  dry  benzene  solu- 
tion as  described  in  the  preparation  of  the  dimethyl  ester.  A much  more  vigorous 


$ 


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22 


reaction  occurred,  sufficient  heat  being  produced  to  boil  the  benzene. 

The  color  of  the  mixture  turned  from  pale  yellow  to  a deep  reddish 
brown  but  there  was  no  crystallization  nor  any  evidence  of  the  separation  of  an 
oil.  Even  after  standing  for  several  hours,  the  benzene  solution  appeared  quite 
homogeneous. 

To  remove  the  benzene,  the  mixture  was  heated  on  a water  bath.  A 
quantitative  yield  of  condensation  product  was  obtained. 

The  hydrochloride  of  the  nitro  ester  is  a viscous  oil  with  no  apparent 
tendency  to  crystallization.  Even  cooling  to  low  temperatures  failed  to  bring 
crystals. 


(4)  Preparation  of  di-normal  amyl  amino 
ethyl  para  amino  benzoate. 

The  reduction  of  21.7  g.  of  the 


/ 

p-no2-c6h4-c-g-gf2-ch2-it  C 


°V  CVGVGVGH3 

CH2-  CF2-CE2-CH2-CH3 


-HCl 


was  carried  out  by  iron  as  described  under  the  reduction  of  the  di  methyl  com- 
pound. There  were  no  variations  observed  in  the  two  reductions. 

The  amino  ester  was  washed  out  as  the  tartrate  and  extracted  with 
ether  after  being  freed  with  alkali.  The  further  extraction  of  the  reduction 
mass  by  direct  treatment  with  ether  gave  enough  of  the  ester  to  make  it  appear 
probable  that  direct  extraction  would  be  more  successful  with  this  than  v/ith  the 
dimethyl  ester.  The  yield  of  free  ester  was  14.3  g.  (72.8%). 

Di  normal  amyl  amino  ethyl  p-amino  benzoate  is  a viscous  oil,  rather 
dark  brown  as  obtained  by  extraction.  It  appears  probable,  however,  that  it  is 
colorless  whan  pure.  It  showed  no  tendency  toward  crystallization.  Applied  to 


23 


the  tongue , it  has  a hitter  taste  — this  my  he  due  to  impurities  — and  some- 
what slowly  produces  very  complete  insensibility  in  the  area  to  which  it  has 
been  applied. 


(5)  Preparation  of  di  normal  amyl  amino  ethyl 
para  amino  benzoate  monochlorhydrate. 

The  free  ester  was  dissolved  in  alcohol  and  titrated  with  alcoholic 
ECl  until  neutral  to  litmus.  The  alcohol  was  then  evaporated  and  the  oily  resi- 
due allowed  to  stand.  After  some  time  crystallization  slowly  began  and  after 
about  a day  the  vfoole  mass  had  crystallized. 

It  forms  clear,  transparent,  needle-like  crystals  melting  at  112.5°. 
Because  of  its  low  solubility  in  cold  water,  recrystallization  from  that  radium 
can  be  satisfactorily  employed.  Care  must  be  taken,  however,  that  the  hydrochlor 
ide  is  not  taken  into  solution  in  too  hot  water  (about  50°  - 60°  appears  best) 
or  hydrolysis  is  apt  to  occur  and  the  resulting  product  will  be  very  hard  to 
purify.  > 

The  hydrochloride  thus  prepared  is  rather  bitter  but  produces  vary 
marked  and  long-lasting  anesthetic  effects  upon  the  tongue. 


Amount  taken. 

Nitrogen 
N calculated. 

N found. 

.2242  g. 

.01762 

.0181 

.2074  g. 

.01626 

.0166 

(c)  Preparation  of  di  iso  amyl  amine. 

A modified  Hofmann  condensation  was  used  in  the  synthesis  of  this 
amine.  Because  of  the  failure  of  the  various  types  of  pressure  flasks  used  in 
the  experiments  to  hold  without  leaking  or  to  withstand  the  pressures  produced 


24 

no  quantitative  data  on  the  synthesis  of  the  primary  amine  were  obtained.  The 
method  was,  however,  to  seal  iso-amyl  bromide  with  a saturated  solution  of  am- 
monia in  ethyl  aloohol  and  heat  in  a water  bath. 

None  of  the  pressure  flasks  oame  thru  intact  but  some  of  the  hydro- 
bromide was  obtained  in  each  condensation.  From  these  mixtures  20.5  g.  of  a 

fraction  boiling  from  90°  - 95°  was  obtained.  The  boiling  point  of  primary  iso 
n 49 

amyl  amine  is  95  . 

This  was  refluxed  with  55.6  g.  of  iso-amyl  bromide  but  distillation 
gave  no  fraction  with  a boiling  point  near  that  of  the  secondary  iso  amyl  amine — 
187°.  It  thus  appears  lhat  this  rrethod  is  not  as  easily  applicable  to  the  sec- 
ondary iso  amyl  amine  as  to  the  secondary  normal  amyl  amine.  It  may  be,  however, 
that  the  method  is  not  at  fault  and  that  the  difficulty  lay  in  the  impurity  of 
the  iso  amyl  bromide  employed.  The  bromide  used  in  these  experiments  was  found 
to  contain  about  20^  active  amyl  bromide  and  it  seems  very  probable  that  this  in- 
terfered with  the  reaction.  It  does  not  seem  that  the  condensation  should  pro- 
ceed more  slowly  or  with  greater  difficulty  for  the  iso  amyl  than  for  the  normal. 

The  primary  amine  recovered  in  the  above  distillation  was  sealed  in 
a Carius  tube  with  the  theoretical  amount  of  iso  amyl  bromide  (the  same  grade  as 
before)  and  heated  to  above  150°  for  eight  hours.  From  this  mixture  3.2  g.  of 
secondary  iso  amyl  amine  boiling  at  185°  - 190°  was  obtained. 


25 

V.  SUMMARY. 

It  was  planned,  to  synthesize  a series  of  local  anesthetics  of  the  pro- 
caine type  in  order  to  determine  what  relations,  if  any,  existed  between  chemi- 
cal constitution,  physical  properties  and  physiological  action.  This  research 
undertook  the  synthesis  of  the  dimethyl,  dinormal  amyl  and  diiso  amyl  compounds. 

The  dimethyl  and  dinomial  amyl  compounds  were  prepared  and  character- 
ized. Certain  difficulties  prevented  the  completion  of  the  work  on  the  diiso 
amyl  compound.  This  synthesis  will  be  completed  and  reported  later. 

The  dimethyl  e3ter  melts  at  a higher  temperature  than  the  dinormal 
amyl  ester;  its  solubility  is  much  greater;  its  anestheticity  is  much  less. 

Further  studies  will  be  made  to  determine  accurately  other  physical 
properties.  These  data  together  with  the  pharmacodynamic  data  which  will  be  de- 
termined in  another  laboratory  will  be  reported  as  soon  as  available. 


26 

VI.  BIBI  IOGBAPHY. 

1.  Niemann  - Ann.,  114,  213  (1860) 

2.  Einhom  - Ann.,  311,  26  (1900) 

3.  Merck  - B.,  18,  2264  and  2952  (1885) 

4.  Willstaetter  - Ann.,  326,  42  (1902) 

5.  Einhom  - Ann.,  371,  125  (1909) 

6.  D R P,  90245 

7.  Vinci  - Virchow’s  Archiv.,  45,  78 

8.  Einhorn  and  Pyle  - Ann.,  311,  34  (1900) 

9.  Kamm  - J.  A.  C.  S. , 42,  1030  (1920) 

10.  Kamm,  Adams  and  Volwiler  - U.  3.,  1,358,751  (1920) 

11.  Verwom  - ’’irritability'’  - Yale  University  Press  (1913). 

12.  Burge  - Am.  J.  physiol.,  45,  388 

13.  Mathews  - int.  Zeit.  Phys.  Chem.  Biol.,  1,  433  (1914) 

14.  Overton  - ’’Studien  fiber  die  Narkose”  - Gustave  Fischer,  Jena  (1901). 

15.  Meyer  - Arch.  Exp.  path,  pharm. , v.  42  (1899) 

16.  Lillie  - Sci.,  37,  764  and  959 

17. Winterstein  - Biochem.  Zeitsch.,  75,  71  (1916) 

18.  Clowes  - Proc.  Soc.  Exp.  Biol.  Med.,  11,  10 

19.  Brit.,  14,493  (1913) 

20.  7/e  mar  - J.  C.  S.,  HI,  644  (1917) 

21.  Loeffler  - B.,  43,  2031 

22.  Mailhe  - Bui.  Soc . Chem.,  15,  327 

23.  Merz  and  Gasiorowski  - B.,  17,  326 

24.  Sabatier  and  Mailhe  - Compt.  Rend.,  148,898 


r ■■ 


.1 

i-  < 

' ■ > V 

1r  < l : ’li  ■ 


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, 


, 


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* 


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f ' 


. 


>,“>  . . 


. 

< 


27 

25. 

Sabatier  and  Senderens  - Corapt.  Rend.,  140,  482  (1905) 

26. 

von  Braun  - B. , 43,  3209 

27. 

Traube  and  Englehardt  - D R P,  17,205 

28. 

Traube  and  Englehardt  - B.,  44,  3149 

29. 

D HP)  105,870 

30. 

Hofmann  - J.  C.  S. , 3,  300  (1849) 

31. 

Vander  Zande  - Reo.  Trav.  Chim. , 8,  202  (1889) 

32. 

Reilly  and  Hickinbottom  - J.  C.  S. , (trans.  1918)  98. 

33. 

Brazier  and  Wood  - J.  Soc.  Chem.  Ind. , 35,  147 

34. 

Knorr  - B.,  30,  911  (1897) 

35. 

Wurtz  - Ann.,  121,  226  (1862) 

36. 

Meyer  and  Jaoobson  - 2,  543 

37. 

Einhorn  - Ann.,  371,  135  (1910) 

38. 

Ibid,  371,  135 

39. 

E R P,-  187,593  (1906) 

40. 

Einhom  - Ann.,  371,  135 

43.. 

D2P  - 180,292 

* 

42. 

Einhorn  - Ann.,  371,  131 

43. 

D R P - 194,748 

44. 

D R P - 179,627 

45. 

Einhorn  - Ann.,  371,  131  (1910) 

46. 

Kamm  and  Marvel  - J.  A.  G.  S* , 42,  299  (1920) 

47. 

Hofmann  - B. , 770 

CD 

• 

Stalzner  - Part  II,  1155 

49. 

Wurtz  - Ann.,  76,  334 

